GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity

Abstract

N-Methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity is a strong candidate to mediate learning and memory processes that require the hippocampus. This plasticity is bidirectional, and how the same receptor can mediate opposite changes in synaptic weights remains a conundrum. It has been suggested that the NMDAR subunit composition could be involved. Specifically, one subunit composition of NMDARs would be responsible for the induction of long-term potentiation (LTP), whereas NMDARs with a different subunit composition would be engaged in the induction of long-term depression (LTD). Unfortunately, the results from studies that have investigated this hypothesis are contradictory, particularly in relation to LTD. Nevertheless, current evidence does suggest that the GluN2B subunit might be particularly important for plasticity and may make a synapse bidirectionally malleable. In particular, we conclude that the presence of GluN2B subunit-containing NMDARs at the postsynaptic density might be a necessary, though not a sufficient, condition for the strengthening of individual synapses. This is owing to the interaction of GluN2B with calcium/calmodulin-dependent protein kinase II (CaMKII) and is distinct from its contribution as an ion channel.

Keywords: NMDA receptor subunit; hippocampus; learning; plasticity.

Figure 1.

NMDA receptor location and subunits in synaptic plasticity. (a) NMDARs are found both pre- and postsynaptically, and these two NMDAR populations might play different roles in synaptic plasticity. In the postsynaptic membrane, NMDARs are found synaptically, perisynaptically and extrasynaptically, where they are also likely to perform different functions. (b) During induction of spike timing-dependent LTP, Ca²⁺ influx through GluN2B subunit-containing NMDARs (orange arrow) directly activates CaMKII to trigger LTP. Tetanic activation elicits a larger Ca²⁺ influx through GluN2A subunit-containing NMDARs (grey arrows), which reaches and activates CaMKII anchored at the postsynaptic density (PSD) by the C-terminal of the GluN2B subunit. In both cases, it is CaMKII activation that triggers downstream signalling cascades mediating LTP expression, suggesting that the presence of the GluN2B subunit at the PSD is important for LTP induction irrespective of whether it supports a majority of the Ca²⁺ influx.